Biomedical subjects
Publications and source records attributed to R Guillemin.
Profound and long-lasting analgesia (mean duration of pain relief 33.4 h, range 22.5--73.5 h) was produced by intrathecal administration of 3 mg synthetic beta-endorphin in all of 14 patients with intractable pain due to disseminated cancer. No respiratory depression, hypotension, hypothermia, or catatonia was observed.
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Basal levels of immunoreactive (ir) beta-endorphin, corticotropin (ACTH), and prolactin (PRL) in plasma of male rats decrease after dexamethasone pretreatment (400 microgram/kg at 24 hr and 200 microgram/kg at 2 hr before). Inescapable electric footshocks increase ir-beta-endorphin, ACTH, and PRL plasma levels and this effect is blocked by dexamethasone pretreatment. Morphine (20 mg/kg) also increases ir-beta-endorphin, ACTH, and PRL levels. Dexamethasone pretreatment blocks the morphine-induced release of ir-beta-endorphin but does not prevent the morphine-induced release of PRL. Naloxone, the opiate antagonist, decreases basal plasma levels of PRL and partially blocks the stress-induced increase of PRL, but it has no effect on the basal or stress-induced release of ir-beta-endorphin. These results are consistent with the proposal that beta-endorphin may interact with an opiate receptor involved in the regulation of PRL secretion.
The primary structure of the NH2-terminally extended somatostatins isolated from ovine hypothalamic extracts, one containing 28 residues and the other 25, has been determined. The structure of somatostatin-28 is Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH; the shorter one, somatostatin-25, has the same sequence as somatostatin-28 except that the first three NH2-terminal residues are deleted. The two peptides as isolated were found to be oxidized at the methionine residue to the methionine sulfoxide. Their structures were established by subjecting the native peptides to direct sequence analysis in a Beckman 890C sequencer and identifying the released phenylthiohydantoin derivatives by high-performance liquid chromatography. Their structures were confirmed by trypsin digestion and isolation of all the tryptic peptides, followed by amino acid analysis of the tryptic fragments. Moreover, some of the tryptic peptides were matched with their respective synthetic replicates on high-performance liquid chromatography.
A novel method for the separation of peptides from amino acids and salts has been developed. Separation is achieved by passage of the sample through a column of octadecasilyl-silica (ODS). Peptides, but not amino acids and salts, are strongly retained by ODS in an aqueous mobile phase and can be recovered by elution with an aqueous-alcoholic mobile phase. The method is applicable to most peptides and is fast and simple. Moreover, it is characterized by good recovery yields and high sample capacity.
A peptide representing the major form of somatostatin-like immunoreactivity was isolated from 600 rat pancreata by using anti-somatostatin affinity chromatography, gel permeation chromatography and reverse-phase high-performance liquid chromatography (HPLC). The isolated peptide elutes with the same retention time as synthetic somatostatin-14 in isocratic HPLC and its amino acid composition is in agreement with that of the tetradecapeptide. We propose that the structure of the major rat pancreatic somatostatin is identical to that of somatostatin-14 characterized in other species.
The distribution of the endorphins, beta-endorphin and enkephalin (Met5-enkephalin and Leu5-enkephalin), was determined in the pars distalis, intermedia, and nervosa of the rat pituitary using both immunocytochemical and radioimmunological methods. Immunoreactive (ir) beta-endorphin was found in pars distalis and pars intermedia. On gel filtration of the pars distalis extracts, beta-endorphin immunoreactivity was eluted in three peaks corresponding to pro-opiocortin (5%), beta-lipotropin (75%), and beta-endorphin (20%). beta-Endorphin was the only component in the pars intermedia. Enkephalin was found in high amount in the pars nervosa. A new enkephalinergic hypothalamic-pars nervosa pathway was observed. Dehydration experiments on normal rats and analysis of the genetically polyuric Brattleboro rat suggest that this enkephalinergic pathway may modulate neurohypophyseal neurosecretion.
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Radioimmunoassay and microdissection procedures were used to study the perinatal development of the endorphin- and enkephalin-containing systems in the rat brain. In contrast to values reported on adult rat, endorphin levels are much higher than enkephalin levels on embryonic day 16. The highest endorphin values are found in the diencephalon, midline telencephalon and medulla-midbrain regions. Perinatally, enkephalin content increases at a faster rate than endorphin in all brain regions, producing a marked drop of the endorphin/enkephalin ratios. Between postnatal days 6 and 25, both endorphin and enkephalin levels increase, approaching their adult distribution pattern. No correlation was found between regional distributions or rates of increase of endorphin and enkephalin in any of these developmental stages, suggesting that the two peptide systems develop independently from each other.
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Crude acetic acid extract of Rat ovaries pretreated with pregnant mare serum (PMSG) contains native peptides with two types of separable biological activities: one, molecular weight greater than 10,000 dalton inhibits the secretion of both LH and FSH as stimulated by luteinizing hormone releasing factor (LRF) in a pituitary monolayer culture system and is referred to as gonadostatin; the other, less than 3,500 dalton, stimulates the secretion of gonadotropins and is designated as gonadocrinin. The biological activities of ovarian gonadocrinin can be competitively inhibited by an LRF-analog-antagonist, D-Phe2, D-Trp6-LRF. These ovarian peptides may participate in physiological control of pituitary LH/FSH secretion.
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The synthesis of four enkephalinamide analogs is described in which the peptide bond between residues 4 and 5 is reversed with or without simultaneous reversal of the carboxyl-terminal amide bond. These so-called partially modified retro-inverso-isomers are new, potent, topochemical analogs of the enkephalins. Tests, both in vitro and in vivo, have shown that these analogs are considerably longer acting than any previously studied enkephalins. Thus, partial reversal of the peptide bonds of the backbone can result in peptides with enhanced activity compared to a parent compound, provide that the structural complementarity of both the side chains and end groups are conserved.
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